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1.
Immunity ; 50(5): 1289-1304.e6, 2019 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-31079916

RESUMEN

Pathogenic lymphocytes initiate the development of chronic inflammatory diseases. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) (encoded by Csf2) is a key communicator between pathogenic lymphocytes and tissue-invading inflammatory phagocytes. However, the molecular properties of GM-CSF-producing cells and the mode of Csf2 regulation in vivo remain unclear. To systematically study and manipulate GM-CSF+ cells and their progeny in vivo, we generated a fate-map and reporter of GM-CSF expression mouse strain (FROG). We mapped the phenotypic and functional profile of auto-aggressive T helper (Th) cells during neuroinflammation and identified the signature and pathogenic memory of a discrete encephalitogenic Th subset. These cells required interleukin-23 receptor (IL-23R) and IL-1R but not IL-6R signaling for their maintenance and pathogenicity. Specific ablation of this subset interrupted the inflammatory cascade, despite the unperturbed tissue accumulation of other Th subsets (e.g., Th1 and Th17), highlighting that GM-CSF expression not only marks pathogenic Th cells, but that this subset mediates immunopathology and tissue destruction.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-1beta/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Inflamación/genética , Inflamación/patología , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CXCR6/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
2.
J Allergy Clin Immunol ; 143(1): 292-304.e8, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29775636

RESUMEN

BACKGROUND: Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue, Ttc7, result in a multisystemic disease, mostly affecting the epithelial barriers and immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients. OBJECTIVE: We sought to identify whether TTC7A mutations dysregulate epithelial cells only or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations. METHODS: Ttc7-mutated (Ttc7fsn/fsn) mice were crossed to generate double-mutant (Rag2-/-Ttc7fsn/fsn) and triple-mutant (Rag2-/-IL2rg-/-Ttc7fsn/fsn) mice. These models, together with bone marrow chimeras, were used to explore the role of adaptive and innate lymphocytes in the flaky skin phenotype. The effect of the Ttc7fsn/fsn mutation on stromal cells was tested in a xenograft model in conjunction with transcriptomic analysis of Ttc7fsn/fsn fibroblasts. RESULTS: We observed that the severity of epithelial hyperproliferation was accentuated by lymphocytes, whereas the phenotype was not induced by transfer of Ttc7-mutated hematopoietic cells. Furthermore, mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. Ttc7-mutated mouse fibroblasts expressed increased transcript levels of insulin-like growth factor 1 (Igf1) and the antimicrobial protein regenerating islet-derived protein 3γ (Reg3γ). In a xenograft model Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes. Thus Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. CONCLUSION: Our results reveal a previously unsuspected fundamental cell-extrinsic role of Ttc7. We have identified potential candidates for molecularly targeted treatment strategies that will need to be evaluated in future preclinical studies.


Asunto(s)
Proliferación Celular , Dermatitis/inmunología , Células Epiteliales/inmunología , Fibroblastos/inmunología , Enfermedades Genéticas Congénitas/inmunología , Linfocitos/inmunología , Mutación , Proteínas/inmunología , Animales , Células 3T3 BALB , Dermatitis/genética , Dermatitis/patología , Células Epiteliales/patología , Fibroblastos/patología , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Humanos , Linfocitos/patología , Ratones , Ratones Noqueados , Proteínas/genética
3.
Cell Rep ; 25(13): 3564-3572.e4, 2018 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-30590032

RESUMEN

Psoriasis is a chronic relapsing, remitting interleukin (IL)-23/IL-17-driven skin disease mediated by the interplay of T cells and polymorphonuclear granulocytes. Although preclinical studies have provided insights into the mechanisms of disease initiation, the underpinnings of natural disease remission remain largely unknown. Here, we addressed the contribution of regulatory Foxp3+ T cells (Treg cells) in psoriasiform skin inflammation and remission using the Aldara-skin inflammation model in combination with the inducible depletion of Foxp3+ Treg cells. Loss of Treg cells exacerbated skin inflammation, but this did not involve increased γδ T cell expansion or the local production of the psoriasis-associated cytokines IL-17A, IL-17F, and IL-22, which are the main driving forces of disease development. Instead, Treg cells suppressed the infiltration of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells into the lesioned skin, and neutralizing GM-CSF in Treg cell-deficient mice reversed hyper-inflammation, resulting in disease regression. Therefore, we identified a non-redundant role of Treg cells restraining skin inflammation and mediating skin homeostasis.


Asunto(s)
Inflamación/inmunología , Piel/patología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Femenino , Factores de Transcripción Forkhead/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Humanos , Imiquimod/efectos adversos , Inflamación/inducido químicamente , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Pruebas de Neutralización , Fagocitos/patología , Psoriasis/inmunología , Psoriasis/patología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo
4.
Eur J Immunol ; 45(11): 3022-33, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26332438

RESUMEN

Conventional αß T cells have the ability to form a long-lasting resident memory T-cell (TRM ) population in nonlymphoid tissues after encountering foreign antigen. Conversely, the concept of 'innate memory', where the ability of nonadaptive branches of the immune system to deliver a rapid, strengthened immune response upon reinfection or rechallenge, is just emerging. Using the αß T-cell-independent Aldara psoriasis mouse model in combination with genetic fate-mapping and reporter systems, we identified a subset of γδ T cells in mice that is capable of establishing a long-lived memory population in the skin. IL-17A/F-producing Vγ4(+) Vδ4(+) T cells populate and persist in the dermis for long periods of time after initial stimulation with Aldara. Experienced Vγ4(+) Vδ4(+) cells show enhanced effector functions and mediate an exacerbated secondary inflammatory response. In addition to identifying a unique feature of γδ T cells during inflammation, our results have direct relevance to the human disease as this quasi-innate memory provides a mechanistic insight into relapses and chronification of psoriasis.


Asunto(s)
Memoria Inmunológica/inmunología , Psoriasis/inmunología , Piel/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Interleucina-17/biosíntesis , Interleucina-17/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Piel/citología
5.
Cell Rep ; 12(9): 1377-84, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26299968

RESUMEN

Although the importance of reactive astrocytes during CNS pathology is well established, the function of astroglia in adult CNS homeostasis is less well understood. With the use of conditional, astrocyte-restricted protein synthesis termination, we found that selective paralysis of GFAP(+) astrocytes in vivo led to rapid neuronal cell loss and severe motor deficits. This occurred while structural astroglial support still persisted and in the absence of any major microvascular damage. Whereas loss of astrocyte function did lead to microglial activation, this had no impact on the neuronal loss and clinical decline. Neuronal injury was caused by oxidative stress resulting from the reduced redox scavenging capability of dysfunctional astrocytes and could be prevented by the in vivo treatment with scavengers of reactive oxygen and nitrogen species (ROS/RNS). Our results suggest that the subpopulation of GFAP(+) astrocytes maintain neuronal health by controlling redox homeostasis in the adult CNS.


Asunto(s)
Astrocitos/metabolismo , Encéfalo/metabolismo , Neuronas Motoras/metabolismo , Estrés Oxidativo , Animales , Antioxidantes/farmacología , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Muerte Celular , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo
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